The long-term objective of this work is to identify the regulatory mechanisms of endogenous cannabinoid signaling in the neocortex. The endocannabinoids (eCBs), of which N-arachidonyl ethanolamide (anandamide, AEA) and 2-arachidonyl glycerol (2-AG) are the best studied, are cleaved from phospholipid precursors and released on demand from principle cells. The eCBs are then rapidly taken into cells and hydrolyzed, but the role of inactivation in the kinetics of eCB synaptic transmission has not been investigated. Fatty acid amide hydrolase (FAAH) hydrolyzes both AEA and 2-AG in vitro, and both eCBs are thought to reenter cells through a temperature-dependent, saturable, and selective reuptake process. Specific pharmacologic agents are available to inhibit both FAAH and the reuptake process. The proposed experiments intend to make use of these agents, FAAH knockout mice, and whole-cell patch clamp techniques to investigate the role of FAAH (Aim 1) and reuptake (Aim 2) in endocannabinoid signaling between GABAergic interneurons and cortical Layer II/III pyramidal neurons.